The experimental fatty liver produced by orotic acid feeding resembles closely that associated with certain diseased states, such as Reye's syndrome. Detoxification of ammonia is impaired in these diseased states. We propose to determine whether fat accumulation in the liver is responsible for impairment of ammonia detoxification, in a study with the following specific aims: (1) A comparative study of the capacity of normal rats and rats with fatty livers to survive a challenge of ammonium acetate. (2) A comparative study of the effectiveness of urea cycle intermediates in protecting against ammonia toxicity in these rats. (3) Estimation of the activities of the mitochondrial and cytoplasmic portions of the urea cycle in suspended hepatocytes isolated from these animals. (4) A comparison of ammonia detoxification in the fatty livers produced by the administration of orotic acid, 4-pentenoic acid, and by choline deficiency. We have also obtained evidence for inhibition of the mitochondrial carbamoylphosphate synthetase by pyrimidines in intact hepatocytes. Since overproduction of orotic acid often accompanies hyperammonemia, we also propose (5) An examination of the influence of pyrimidines on citrulline production and ureagenesis in the intact hepatocyte. These studies should provide insight into the relationship between fatty metamorphosis of the liver, hyperammonemia, the overproduction of orotic acid, and the capacity of the liver for ureagenesis.